Actions and clinical pharmacology

Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. In patients with overactive bladder, characterized by detrusor muscle instability or hyperreflexia, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and the frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S-isomers. Antimuscarinic activity resides predominantly in the R-isomer. The R-isomer of oxybutynin shows greater selectivity for the M3 and M1 muscarinic subtypes (predominant in bladder detrusor muscle and parotid gland) compared to the M2 subtype (predominant in cardiac tissue). The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies.

OXYTROL (oxybutynin transdermal system) is designed to deliver oxybutynin continuously and consistently over a 3 to 4-day time interval after application to intact skin. The OXYTROL system has a skin contact surface area of 39 cm2 and contains 36 mg of oxybutynin.

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. The average daily dose of oxybutynin absorbed from the 39 cm2 OXYTROL system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm2 surface area, was obtained from analysis of residual oxybutynin content of systems worn over a continuous 4-day interval during 303 separate occasions in 76 healthy volunteers. Following application of the first OXYTROL 3.9 mg/day system, oxybutynin plasma concentrations increase for approximately 24 to 48 hours reaching average maximum concentrations of 3 to 4 ng/mL. Thereafter, steady concentrations are maintained for up to 96 hours. (See PHARMACOLOGY, Pharmacokinetics). Absorption of oxybutynin is bioequivalent when OXYTROL is applied to the abdomen, buttocks or hip.

Indications and clinical use

OXYTROL is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Contraindications

OXYTROL is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions.

OXYTROL is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

Precautions

General:

Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin are used in a hot environment. Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

Cardiovascular:

Caution should be used when prescribing antimuscarinics/anticholinergics to patients with preexisting cardiac diseases.

Hepatic or Renal Impairment:

OXYTROL should be used with caution in patients with hepatic or renal impairment.

Urinary Retention:

OXYTROL should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).

Gastrointestinal Disorders:

OXYTROL should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS). OXYTROL, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

OXYTROL should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

Use in the Elderly:

Of the total number of patients in the clinical studies of OXYTROL, 49% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Use in Children:

The safety and efficacy of OXYTROL in pediatric patients have not been established.

Use in Pregnancy:

The safety of OXYTROL administration to women who are or who may become pregnant has not been established. Therefore, OXYTROL should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.

Nursing Mothers:

It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when OXYTROL is administered to a nursing woman.

Dependence Liability:

OXYTROL (Oxybutynin Transdermal System) has a low potential for abuse. Oxybutynin is an anticholinergic compound with a well known safety and efficacy profile. The compound does not possess characteristics commonly associated with drugs of dependence liability or abuse, such as those with euphoric, central nervous system (CNS) depressant, or stimulant action.

Drug Interactions:

The concomitant use of oxybutynin with other anticholinergic drugs or with other agents that produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects.

Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Pharmacokinetic studies with patients concomitantly receiving cytochrome P450 enzyme inhibitors, such as antimycotic agents (e.g. ketoconazole, itraconazole, and miconazole) or macrolide antibiotics (e.g. erythromycin and clarithromycin), have not been performed.

Adverse reactions

The safety of OXYTROL was evaluated in a total of 417 patients who participated in two Phase III clinical efficacy and safety studies and an open-label extension. Additional safety information was collected in Phase I and Phase II trials. In the two pivotal studies, (Study 1 and Study 2; see Clinical Studies section of the Product Monograph), a total of 246 patients received OXYTROL during the 12-week treatment periods. A total of 411 patients entered the open-label extension and of those, 65 patients and 52 patients received OXYTROL for at least 24 weeks and at least 36 weeks, respectively.

No deaths were reported during treatment. No serious adverse events related to treatment were reported.

Adverse events reported in the pivotal trials are summarized in Tables 1 and 2 below.

Table 1: Number (%) of adverse events occurring in ≥ 2% of OXYTROL-treated patients and greater in OXYTROL group than in placebo group (Study 1).

Adverse Event*

Placebo (N = 132)

OXYTROL (3.9 mg/day) (N = 125)

N

%

N

%

Application site pruritus

8

6.1

21

16.8

Dry mouth

11

8.3

12

9.6

Application site erythema

3

2.3

7

5.6

Application site vesicles

0

0.0

4

3.2

Diarrhea

3

2.3

4

3.2

Dysuria

0

0.0

3

2.4

* includes adverse events judged by the investigator as possibly, probably or definitely treatment-related

Table 2: Number (%) of adverse events occurring in ≥ 2% of OXYTROL-treated patients and greater in OXYTROL group than in placebo group (Study 2).

Adverse Event*

Placebo (N = 117)

OXYTROL (3.9 mg/day) (N = 121)

N

%

N

%

Application site pruritus

5

4.3

17

14.0

Application site erythema

2

1.7

10

8.3

Dry mouth

2

1.7

5

4.1

Constipation

0

0.0

4

3.3

Application site rash

1

0.9

4

3.3

Application site macules

0

0.0

3

2.5

Abnormal vision

0

0.0

3

2.5

* includes adverse events judged by the investigator as possibly, probably or definitely treatment-related

Other adverse events reported by > 1% of OXYTROL-treated patients, and judged by the investigator to be possibly, probably or definitely related to treatment include: abdominal pain, nausea, flatulence, fatigue, somnolence, headache, flushing, rash, application site burning and back pain.

Most treatment-related adverse events were described as mild or moderate in intensity. Severe application site reactions were reported by 6.4% of OXYTROL-treated patients in Study 1 and by 5.0% of OXYTROL-treated patients in Study 2.

Treatment-related adverse events that resulted in discontinuation were reported by 11.2% of OXYTROL-treated patients in Study 1 and 10.7% of OXYTROL-treated patients in Study 2. Most of these were secondary to application site reaction. In the two pivotal studies, no patient discontinued OXYTROL treatment due to dry mouth.

In the open-label extension, the most common treatment-related adverse events were: application site pruritus, application site erythema and dry mouth.

Symptoms and treatment of overdosage

Overdosage using OXYTROL (oxybutynin transdermal system) is unlikely. Each 39 cm2 system contains 36 mg oxybutynin and delivers 3.9 mg/day when attached to the skin. Thus, 36 mg oxybutynin would be the maximum dose possible if a system were inadvertently taken internally. In terms of transdermal application, if an entire box of 24 systems were applied simultaneously and worn for 24 hours, the resulting dose would be 93.6 mg.

Case reports of oral overdose with oxybutynin chloride indicate that doses of this magnitude should resolve with withdrawal of exposure and supportive care. Overdose with oral oxybutynin chloride has been associated with anticholinergic effects including central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oral oxybutynin chloride in association with alcohol has been reported in a 13-year-old boy who experienced memory loss, and a 34-year-old woman who developed stupor, following by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients recovered fully with symptomatic treatment.

In the event of a possible overdose, the transdermal system(s) should be removed immediately and medical attention sought. Plasma concentrations of oxybutynin and N-desethyloxybutynin decline within 1 to 2 hours after removal of transdermal system(s). If an overdose is suspected, patients should be monitored until symptoms resolve.

For management of a suspected overdose, contact a regional Poison Control Centre.

Dosage and administration

OXYTROL (oxybutynin transdermal system) is designed to deliver oxybutynin continuously and consistently over a 3 to 4-day time interval after application to intact skin. The OXYTROL system has a nominal in vivo delivery rate of 3.9 mg oxybutynin per day through skin of average permeability (interindividual variation in skin permeability is approximately 20%) and contains 36 mg of oxybutynin. OXYTROL adheres well to the skin when applied according to instructions (see Administration below).

Usual Adult Dosage

Administration

OXYTROL should be applied to dry, intact skin on the abdomen, hip or buttock. Apply immediately after removal from the protective pouch. A new application site should be selected with each new OXYTROL system to avoid re-application to the same site within 7 days.